To understand the molecular mechanisms regulating pancreatic endocrine development and function, pancreatic gene expression was compared between Ngn3-deficient mice and littermate controls on embryonic days 13 and 15. Microarray analysis identified 504 genes with significant differences in expression. Fifty-two of these showed at least twofold reduction in Ngn3 knockouts compared to controls. Many of them were previously described to be involved in endocrine development and function. Among the genes not previously characterized were Rhomboid veinlet-like 4, genes involved in tetrahydrobiopterin biosynthesis and the Iroquois-type homeobox gene Irx1, the latter was selected for further investigation. In situ hybridisation demonstrated that two Iroquois genes, Irx1 and Irx2, were expressed in pancreatic endoderm of wild-type, but not Ngn3 mutant embryos. Furthermore, ectopic Ngn3 induced prominent Irx2 expression in chicken endoderm. Co-labelling established that Irx1 and Irx2 mRNA is located to glucagon-, but not insulin- or somatostatin-producing cells in mice and chicken. These data suggest that Irx1 and Irx2 serve an evolutionary conserved role in the regulation of α-cell-specific gene expression.
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- Abstract: Diabetes x
- Abstract: Islets x
- Abstract: Insulin x
- Abstract: BetaCells x
- Abstract: Pancreas x
- Abstract: Obesity x
- Abstract: Glucose x
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- Abstract: Hypoglycemia x
- Abstract: Insulinoma x
- Abstract: Glucagon x
- Abstract: IGF* x
- Abstract: Type 1 x
- Abstract: Type 2 x
Andreas Petri, Jonas Ahnfelt-Rønne, Klaus Stensgaard Frederiksen, David George Edwards, Dennis Madsen, Palle Serup, Jan Fleckner and R Scott Heller
Paola Moreno, Bernardo Nuche-Berenguer, Irene Gutiérrez-Rojas, Alicia Acitores, Verónica Sancho, Isabel Valverde, Nieves González and María L Villanueva-Peñacarrillo
Exendin-4 (Ex-4) mimics glucagon-like peptide-1 (GLP-1 or GCG as listed in the HUGO database), being anti-diabetic and anorectic, in stimulating glucose and lipid metabolism in extrapancreatic tissues. We studied the characteristics of Ex-4 and GLP-1 action, during prolonged treatment, on GLUTs expression (mRNA and protein), glycogen content (GC), glucose transport (GT), glycogen synthase a (GSa), and kinase (PI3K and MAPKs) activity, in liver, muscle, and fat of insulin-resistant (IR, by fructose) and type 2 diabetic (T2D, streptozotocin at birth) rats compared with normal rats. In both IR and T2D, the three tissues studied presented alterations in all measured parameters. In liver, GLP-1 and also Ex-4 normalized the lower than normal Glut2 (Slc2a2) expression and showed a trend to normalize the reduced GC in IR, and GLP-1, like Ex-4, also in T2D, effects mediated by PI3K and MAPKs. In skeletal muscle, neither GLP-1 nor Ex-4 modified Glut4 (Slc2a4) expression in either experimental model but showed normalization of reduced GT and GSa, in parallel with the normalization of reduced PI3K activity in T2D and MAPKs in both models. In adipose tissue, the altered GLUT4 expression in IR and T2D, along with reduced GT in IR and increased GT in T2D, and with hyperactivated PI3K in both, became normal after GLP-1 and Ex-4 treatment; yet, MAPKs, that were also higher, became normal only after Ex-4 treatment. The data shows that Ex-4, as well as GLP-1, exerts a normalizing effect on IR and T2D states through a distinct post-receptor mechanism, the liver being the main target for Ex-4 and GLP-1 to control glucose homeostasis.
Yanyan Cao, Yunsheng Li, Jaekyung Kim, Yulin Ren, Klaus Himmeldirk, Yi Liu, Yanrong Qian, Fengming Liu and Xiaozhuo Chen
Type 2 diabetes (T2D) has become an epidemic worldwide while T1D remains a great medical challenge. Insulin receptor (IR) signaling activators could alleviate hyperglycemia, reduce the burden on the pancreas, and contribute to prevention and treatment of both types of diabetes. Previously, we reported the synthesis and identification of a natural antidiabetic compound α-penta-galloyl-glucose (α-PGG). Subsequent studies led to the identification of an α-P6GG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-d-glucopyranose (6Cl-TGQ). Here, we report that 6Cl-TGQ not only induced rapid and long-lasting glucose uptake comparable to insulin in adipocytes but also reduced high blood glucose levels to near normal and significantly decreased plasma insulin levels and improved glucose tolerance performance in high-fat diet-induced T2D mice when administered orally at 5 mg/kg once every other day. Moreover, a single gavage of 6Cl-TGQ at 10 mg/kg induced rapid and sharp decline of blood glucose in streptozotocin-induced T1D mice. Our studies further indicated that 6Cl-TGQ activated IR signaling in cell models and insulin-responsive tissues of mice. 6Cl-TGQ-induced Akt phosphorylation was completely blocked by IR and PI3K inhibitors, while the induced glucose uptake was blocked by the same compounds and a Glut4 inhibitor. Receptor binding studies indicated that 6Cl-TGQ bound to IR with a higher affinity than α-PGG. Importantly, 6Cl-TGQ, unlike insulin, selectively induced phosphorylation of IR without activating IGF1R or its signaling and did not increase cancer cell proliferation. These results indicate that 6Cl-TGQ is a potent orally efficacious compound with low carcinogenic potential and may contribute to the prevention and treatment of T1D and T2D.
Lena Espelage, Hadi Al-Hasani and Alexandra Chadt
The two closely related RabGAPs TBC1D1 and TBC1D4 are key signaling factors of skeletal muscle substrate utilization. In mice, deficiency in both RabGAPs leads to reduced skeletal muscle glucose transport in response to insulin and lower GLUT4 abundance. Conversely, Tbc1d1 and Tbc1d4 deficiency results in enhanced lipid use as fuel in skeletal muscle, through yet unknown mechanisms. In humans, variants in TBC1D1 and TBC1D4 are linked to obesity, insulin resistance and type 2 diabetes. While the specific function in metabolism of each of the two RabGAPs remains to be determined, TBC1D1 emerges to be controlling exercise endurance and physical capacity, whereas TBC1D4 may rather be responsible for maintaining muscle insulin sensitivity, muscle contraction, and exercise. There is growing evidence that TBC1D1 also plays an important role in skeletal muscle development, since it has been found to be associated to meat production traits in several livestock species. In addition, TBC1D1 protein abundance in skeletal muscle is regulated by both, insulin receptor and insulin-like growth factor-1 (IGF-1) receptor signaling. This review focuses on the specific roles of the two key signaling factors TBC1D1 and TBC1D4 in skeletal muscle metabolism, development and exercise physiology.
Jong-Ik Hwang, Seongsik Yun, Mi Jin Moon, Cho Rong Park and Jae Young Seong
Glucagon-like peptide 1 (GLP1) is an intestinal incretin that regulates glucose homeostasis through stimulation of insulin secretion from pancreatic β-cells and inhibits appetite by acting on the brain. Thus, it is a promising therapeutic agent for the treatment of type 2 diabetes mellitus and obesity. Studies using synteny and reconstructed ancestral chromosomes suggest that families for GLP1 and its receptor (GLP1R) have emerged through two rounds (2R) of whole genome duplication and local gene duplications before and after 2R. Exon duplications have also contributed to the expansion of the peptide family members. Specific changes in the amino acid sequence following exon/gene/genome duplications have established distinct yet related peptide and receptor families. These specific changes also confer selective interactions between GLP1 and GLP1R. In this review, we present a possible macro (genome level)- and micro (gene/exon level)-evolution mechanisms of GLP1 and GLP1R, which allows them to acquire selective interactions between this ligand–receptor pair. This information may provide critical insight for the development of potent therapeutic agents targeting GLP1R.
Sufang Chen, Wei Wei, Minjie Chen, Xiaobo Qin, Lianglin Qiu, Li Zhang, Yuhao Zhang, Qi Cao and Zhekang Ying
Numerous studies have implicated tumor necrosis factor α (TNFα) in the pathogenesis of type 2 diabetes. However, the role of its primary receptor, TNF receptor 1 (TNFR1), in homeostatic regulation of glucose metabolism is still controversial. In addition to TNFα, lymphotoxin α (LTα) binds to and activates TNFR1. Thus, TNFα and LTα together are known as TNF. To delineate the role of TNF signaling in glucose homeostasis, the present study ascertained how TNF signaling deficiency affects major regulatory components of glucose homeostasis. To this end, normal diet-fed male TNFR1-deficient mice (TNFR1−/−), TNFα/LTα/LTβ triple-deficient mice (TNF/LT∆3) and their littermate controls were subjected to intraperitoneal glucose tolerance test, insulin tolerance test and oral glucose tolerance test. The present results showed that TNFR1−/− and TNF/LT∆3 mice vs their controls had comparable body weight, tolerance to intraperitoneal glucose and sensitivity to insulin. However, their tolerance to oral glucose was significantly increased. Additionally, glucose-induced insulin secretion assessments revealed that TNFR1 or TNF/LT deficiency significantly increased oral but not intraperitoneal glucose-induced insulin secretion. Consistently, qPCR and immunohistochemistry analyses showed that TNFR1−/− and TNF/LT∆3 mice vs their controls had significantly increased ileal expression of glucagon-like peptide-1 (GLP-1), one of the primary incretins. Their oral glucose-induced secretion of GLP-1 was also significantly increased. These data collectively suggest that physiological TNF signaling regulates glucose metabolism primarily through effects on GLP-1 expression and secretion and subsequently insulin secretion.
Hanze Du, Limei Liu, Ying Wang, Yuichi Nakagawa, Alexei Lyzlov, Kabirullah Lutfy, Theodore C Friedman, Xiaozhong Peng and Yanjun Liu
Pre-receptor activation of glucocorticoids via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 (HSD11B1)) has been identified as an important mediator of the metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) mediates 11β-HSD1 amplifying tissue glucocorticoid production by driving intracellular NADPH exposure to 11β-HSD1 and requires glucose-6-phosphate transporter (G6PT (SLC37A4)) to maintain its activity. However, the potential effects of G6PT on tissue glucocorticoid production in type 2 diabetes and obesity have not yet been defined. Here, we evaluated the possible role of G6PT antisense oligonucleotides (G6PT ASO) in the pre-receptor metabolism of glucocorticoids as related to glucose homeostasis and insulin tolerance by examining the production of 11β-HSD1 and H6PDH in both male db/ + and db/db mouse liver tissue. We observed that G6PT ASO treatment of db/db mice markedly reduced hepatic G6PT mRNA and protein levels and substantially diminished the activation of hepatic 11β-HSD1 and H6PDH. Reduction of G6pt expression was correlated with the suppression of both hepatic gluconeogenic enzymes G6Pase and PEPCK and corresponded to the improvement of hyperglycemia and insulin resistance in db/db mice. Addition of G6PT ASO to mouse hepa1–6 cells led to a dose-dependent decrease in 11B-Hsd1 production. Knockdown of G6PT with RNA interference also impaired 11B-Hsd1 expression and showed comparable effects to H6pdh siRNA on silencing of H6pdh and 11B-Hsd1 expression in these intact cells. These findings suggest that G6PT plays an important role in the modulation of pre-receptor activation of glucocorticoids and provides new insights into the role of G6PT in the development of type 2 diabetes.
Yu-Feng Zhao, Damien J Keating, Maria Hernandez, Dan Dan Feng, Yulong Zhu and Chen Chen
Dysfunction of pancreatic β-cells is a fundamental feature in the pathogenesis of type 2 diabetes. As insulin receptor signaling occurs via protein tyrosine kinase (PTK), we investigated the role of PTK activity in the etiology of β-cell dysfunction by inhibiting PTK activity in primary cultured mouse pancreatic β-cells and INS-1 cells with genistein treatment over 24 h. Electrophysiologic recordings showed genistein treatment significantly attenuated ATP-sensitive K+ (KATP) and voltage-dependent Ca2+ currents, and depolarized the resting membrane potential in primary β-cells. When stimulated by high glucose, genistein-treated β-cells exhibited a time delay of both depolarization and Ca2+ influx, and were unable to fire action potentials, as well as displaying a reduced level of Ca2+ influx and a loss of Ca2+ oscillations. Semiquantitative PCR analysis revealed decreased expression of KATP and L-type Ca2+ channel mRNA in genistein-treated islets. PTK inhibition also significantly reduced the rapid component of secretory vesicle exocytosis, as indicated by membrane capacitance measurements, and this is likely to be due to the reduced Ca2+ current amplitude in these cells. These results illustrate that compromised PTK activity contributes to pancreatic β-cell dysfunction and may be involved in the etiology of type 2 diabetes.
Suwattanee Kooptiwut, Melkam Kebede, Sakeneh Zraika, Sherley Visinoni, Kathryn Aston-Mourney, Jenny Favaloro, Chris Tikellis, Merlin C Thomas, Josephine M Forbes, Mark E Cooper, Marjorie Dunlop, Joseph Proietto and Sofianos Andrikopoulos
Type 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2.8 mM glucose) insulin release was increased in both DBA/2 and C57BL/6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BL/6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.
Kira Meyerovich, Fernanda Ortis, Florent Allagnat and Alessandra K Cardozo
Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.